Nickel Compounds

Hazard Summary-Created in April 1992; Revised in January 2000

Nickel occurs naturally in the environment at low levels. Nickel
is an essential element in some animal species, and it has been suggested
it may be essential for human nutrition. Nickel dermatitis, consisting
of itching of the fingers, hands, and forearms, is the most common effect
in humans from chronic (long-term) skin contact with nickel. Respiratory
effects have also been reported in humans from inhalation exposure to
nickel. Human and animal studies have reported an increased risk
of lung and nasal cancers from exposure to nickel refinery dusts and nickel
subsulfide. Animal studies of soluble nickel compounds (i.e., nickel
carbonyl) have reported lung tumors. EPA has classified nickel refinery
dust and nickel subsulfide as Group A, human carcinogens, and nickel carbonyl
as a Group B2, probable human carcinogen.

Sources and Potential Exposure

Nickel is a natural element of the earth's crust; therefore, small
amounts are found in food, water, soil, and air. (6)

Food is the major source of nickel exposure, with an average intake
for adults estimated to be approximately 100 to 300 micrograms per day
(µg/d). (1,6)

Individuals also may be exposed to nickel in occupations involved
in its production, processing, and use, or through contact with everyday
items such as nickel-containing jewelry and stainless steel cooking
and eating utensils, and by smoking tobacco. (1)

Nickel is found in ambient air at very low levels as a result of
releases from oil and coal combustion, nickel metal refining, sewage
sludge incineration, manufacturing facilities, and other sources. (2,6)

Given its high instability, nickel carbonyl exposure is extremely
rare.

Assessing Personal Exposure

Health Hazard Information

Acute Effects:

One person exposed to an extrememly high level of nickel by inhalation
suffered severe damage to the lungs and kidneys. (6)

Gastrointestinal distress (e.g., nausea, vomiting, diarrhea) and
neurological effects were reported in workers who drank water on one
shift that was contaminated with nickel as nickel sulfate and nickel
chloride. (1,6)

Pulmonary fibrosis and renal edema were reported in humans and animals
following acute (short-term) exposure to nickel carbonyl. (1)

Acute animal tests in rats have shown nickel compounds to exhibit
acute toxicity values ranging from low
to high. The soluble compounds, such
as nickel acetate, were the most toxic, and the insoluble forms, such
as nickel powder, were the least toxic. (6)

Chronic Effects(Noncancer):

Dermatitis is the most common effect in humans from chronic dermal
exposure to nickel. Cases of nickel dermatitis have been reported following
occupational and non-occupational exposure, with symptoms of eczema
(rash, itching) of the fingers, hands, wrists, and forearms. (1,2,6,7)

Chronic inhalation exposure to nickel in humans also results in respiratory
effects, including a type of asthma specific to nickel, decreased lung
function, and bronchitis. (6,7)

Animal studies have reported effect on the lungs and immune system
from inhalation exposure to soluble and insoluble nickel compounds (nickel
oxide, subsulfide, sulfate heptahydrate). (1,6)

Soluble nickel compounds are more toxic to the respiratory tract
than less soluble compounds. (6)

EPA has not established a Reference Concentration (RfC)
for nickel. (2,3,4,5)

The Reference Dose (RfD)
for nickel (soluble salts) is 0.02 milligrams per kilogram body weight
per day (mg/kg/d) based on decreased body and organ weights in rats.
The RfD is an estimate (with
uncertainty spanning perhaps an order of magnitude) of a daily oral
exposure to the human population (including sensitive subgroups) that
is likely to be without appreciable risk of deleterious noncancer effects
during a lifetime. It is not a direct estimator of risk, but rather
a reference point to gauge the potential effects. At exposures increasingly
greater than the RfD, the potential
for adverse health effects increases. Lifetime exposure above the RfD
does not imply that an adverse health effect would necessarily occur.
(5)

EPA has medium confidence in the RfD
due to: (1) low confidence in the study on which the RfD
for nickel (soluble salts) was based because, although it was properly
designed and provided adequate toxicological endpoints, high mortality
occurred in the controls; and (2) medium confidence in the database
because it provided adequate supporting subchronic studies, one by gavage
and the other in drinking water, but inadequacies in the remaining reproductive
data. (5)

Nickel is an essential nutrient for some mammalian species, and has
been suggested to be essential for human nutrition. By extrapolation
from animal data, it is estimated that a 70-kg person would have a daily
requirement of 50 µg per kg diet of nickel. (6)

The California Environmental Protection Agency
(CalEPA) has calculated a chronic inhalation reference exposure level
of 0.00005 milligrams per cubic meter (mg/m3) for nickel
based on respiratory and immune system effects reported in rats exposed
to a soluble nickel salt. The CalEPA reference exposure level is a concentration
at or below which adverse health effects are not likely to occur. (7)

ATSDR has calculated a chronic-duration inhalation MRL of 0.0002
mg/m3 for nickel based on respiratory effects reported in
rats exposed to a soluble nickel salt. The MRL is an estimate of the
daily human exposure to a hazardous substance that is likely to be without
appreciable risk of adverse noncancer health effects over a specified
duration of exposure. (6)

Reproductive/Developmental Effects:

No information is available regarding the reproductive or developmental
effects of nickel in humans. (6)

Animal studies have reported reproductive and developmental effects,
such as a decreased number of live pups per litter, increased pup mortality,
and reduction in fetal body weight, and effects to the dam from oral
exposure to soluble salts of nickel. (5,6)

Sperm abnormalities and decreased sperm count have been reported
in animals exposed to nickel nitrate orally and nickel oxide by inhalation,
respectively. (6)

Cancer Risk:

Nickel Salts

Nickel sulfate via inhalation and nickel acetate in drinking water
were not carcinogenic in either rats or mice. (6)

EPA has not evaluated soluble salts of nickel as a class of compounds
for potential human carcinogenicity. (5)

Nickel Refinery Dust and Nickel Subsulfide

Human studies have reported an increased risk of lung and nasal cancers
among nickel refinery workers exposed to nickel refinery dust.
Nickel refinery dust is a mixture of many nickel compounds, with nickel
subsulfide being the major constituent. (3,4,6)

Animal studies have also reported lung tumors from inhalation exposure
to nickel refinery dusts and to nickel subsulfide. (3,4)

EPA uses mathematical models, based on animal studies, to estimate
the probability of a person developing cancer from breathing air containing
a specified concentration of a chemical. EPA calculated an inhalation
unit risk estimate of 2.4 × 10-4 (µg/m3)-1
for nickel refinery dusts. EPA estimates that, if an individual
were to continuously breathe air containing nickel refinery dusts at
an average of 0.004 µg/m3 (4 x 10-6 mg/m3)
over his or her entire lifetime, that person would theoretically have
no more than a one-in-a-million increased chance of developing cancer
as a direct result of breathing air containing this chemical. Similarly,
EPA estimates that continuously breathing air containing 0.04 µg/m3
would result in not greater than a one-in-a-hundred thousand increased
chance of developing cancer, and air containing 0.4 µg/m3
would result in not greater than a one-in-ten thousand increased chance
of developing cancer. For a detailed discussion of confidence in the
potency estimates, please see IRIS. (3)

For nickel subsulfide, EPA calculated an inhalation unit risk estimate
of 4.8 x 10-4 (µg/m3)-1. EPA
estimates that, if an individual were to continuously breathe air containing
this nickel compound at an average of 0.002 µg/m3 (2
x 10-6 mg/m3) over his or her entire lifetime,
that person would theoretically have no more than a one-in-a-million
increased chance of developing cancer as a direct result of breathing
air containing this chemical. Similarly, EPA estimates that continuously
breathing air containing 0.02 µg/m3 would result in
not greater than a one-in-a-hundred thousand increased chance of developing
cancer, and air containing 0.2 µg/m3 would result in
not greater than a one-in-ten thousand increased chance of developing
cancer. (4)

ACGIH TLV--American Conference of Governmental and Industrial
Hygienists' threshold limit value expressed as a time-weighted average;
the concentration of a substance to which most workers can be exposed
without adverse effects. NIOSH REL--National Institute of Occupational Safety and Health's
recommended exposure limit; NIOSH-recommended exposure limit for an 8-
or 10-h time-weighted-average exposure and/or ceiling. NIOSH IDLH-- NIOSH's immediately dangerous to life or health concentration;
NIOSH recommended exposure limit to ensure that a worker can escape from
an exposure condition that is likely to cause death or immediate or delayed
permanent adverse health effects or prevent escape from the environment.
OSHA PEL--Occupational Safety and Health Administration's permissible
exposure limit expressed as a time-weighted average; the concentration
of a substance to which most workers can be exposed without adverse effect
averaged over a normal 8-h workday or a 40-h workweek.

The health and regulatory values cited in this factsheet were obtained
in December 1999. aHealth numbers are toxicological numbers from
animal testing or risk assessment values developed by EPA. bRegulatory numbers are values that have been
incorporated in Government regulations, while advisory numbers are nonregulatory
values provided by the Government or other groups as advice. OSHA
numbers are regulatory, whereas NIOSH and ACGIH numbers are advisory.
cThe NOAEL is from the critical study used
as the basis for both the ATSDR chronic MRL and CalEPA chronic reference
exposure level.

References

U.S. Environmental Protection Agency. Health
Assessment Document for Nickel. EPA/600/8-83/012F. National Center
for Environmental Assessment, Office of Research and Development, Washington,
DC. 1986.

National Institute for Occupational Safety and
Health (NIOSH). Pocket
Guide to Chemical Hazards. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention. Cincinnati, OH. 1997.